Doxorubicin was first isolated (albeit in low yield) from the fermentation broth of Streptomyces peucetius var. caesius (U.S. Pat. No. 3,590,028).
Subsequently doxorubicin was synthesized from daunorubicin (U.S. Pat. No. 3,803,124) by halogenation with bromine or iodine in a cyclic ether containing 18-40% of methanol to give the corresponding 14-halo derivative; doxorubicin then was obtained either directly by alkaline hydrolysis of this intermediate or indirectly via 14-acetoxy daunorubicin (obtained by treatment of the 14-halo derivative with an alkali metal acetate in the presence of acetone) which was in turn subjected to alkaline hydrolysis. The overall yields (from daunorubicin hydrochloride to doxorubicin hydrochloride) claimed in the above-mentioned patent are 37% for the direct hydrolysis method (Example 1) but only 0.8% for the method using alkaline hydrolysis of the 14-acetoxy-daunorubicin intermediate (Example 2). In order to overcome the degradative side-reactions the use of various protecting groups was studied (Examples 5 and 6). This complication, however, did not lead to any improvement in the overall yield and indeed the products were isolated, in extremely low yields, only after chromatographic purification.
WO86/00073 claims an improved method for the bromination of daunorubicin hydrochloride using conditions which lead to ketal formation, principally the 13,13-dimethoxy ketal, thus stabilizing the intermediate 14-bromo-daunorubicin. The method described for the conversion of this intermediate into doxorubicin hydrochloride consists of treatment with diluted hydrobromic acid in acetone leading to the free ketone, which is treated without isolation with sodrum formate to give the 14-formyloxy derivative. Hydrolysis of this 14-formyloxy intermediate could be achieved under milder alkaline conditions (pH 7.6 to 8.0) than those used for the hydrolysis of the 14-acetoxy intermediate (pH 10.3). Application of this modified method, however, only gives a very slight improvement in the overall yield from daunorubicin hydrochloride to doxorubicin hydrochloride (increase from 37% to 42.4%).